Comments

The CaS receptor has a number of physiological functions, but it is best known for its central role in parathyroid and renal regulation of extracellular calcium homeostasis [15]. This is seen most clearly in patients with loss-of-function CaS receptor mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutations) or neonatal severe hyperparathyroidism (heterozygous, compound heterozygous or homozygous mutations) [15] and in Casr null mice [5,16], which exhibit similar increases in PTH secretion and blood calcium levels. Gain-of-function CaS mutations are associated with autosomal dominant hypocalcaemia and Bartter syndrome type V [15].

The CaS receptor primarily couples to Gq/11, G12/13 and Gi/o [10,14,17,33], but in some cell types can couple to Gs [23]. However, the CaS receptor can form heteromers with Class C GABAB [6-7] and mGlu1/5 receptors [12], which may introduce further complexity in its signalling capabilities.

Multiple other small molecule chemotypes are positive and negative allosteric modulators of the CaS receptor [18,24]. Further, etelcalcetide is a novel peptide agonist of the receptor [34]. Agonists and positive allosteric modulators of the CaS receptor are termed Type I and II calcimimetics, respectively, and can suppress parathyroid hormone (PTH (PTH, P01270)) secretion [26]. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion [25].

Where functional pKB values are provided for allosteric modulators, this refers to ligand affinity determined in an assay that measures a functional readout of receptor activity (i.e. a receptor signalling assay), as opposed to affinity determined in a radioligand binding assay. The functional pKB may differ depending on the signalling pathway studied. Consult the 'More detailed page' for the assay description, as well as other functional readouts.